Antihypertensive quaternary ammonium salts of 1:2:3:4-tetrahydroisoquinoline



, represent methyl, propargyl or Z-hydroxyethyl groups and X representsThis invention relates to quaternary ammonium salts and pharmaceuticalpreparations containing them.

It has been found that there is a class of quaternary ammonium salts ofl:2:3:4 tetrahydroisoquinoline Whose members modify the actions of thesympathomimetic amines, for example adrenaline, in animals, and

i which class of salts is therefore, of pharmaceutical and veterinaryimportance.

Accordingly, one aspect of the present invention provides apharmaceutical or veterinary composition which United States Patentessentially contains a pharmacologically active quaternaryammonium saltof 1:2:3:4-tetrahydroisoquinoline having the structural formula:

(I) t r wherein R and R which may be the same or different, ethyl,n-propyl, iso-propyl, alkyl,

a non-toxic anion,for example a chloride, bromide or iodide radical, oran alkyl sulphonate or a substituted or unsubstituted aryl sulphonategroup.

Most of such quaternary ammonium salts are believed to benovel compoundsand such of the salts as have been mentioned in the literature have nothad anypharmacological activity attributed to them. The novel saltsprovided by the present invention are quaternary ammonium salts of122:3:4-tetrahydroisoquinoline as defined above except when one of thegroups R, or R con tains one carbon atom and the other group containsfrom one to three carbon atoms or is hydroxyethyl and X is an iodineanion.

As has already been mentioned, the quaternary ammonium salts as definedabove have been found to modify the actions of sympathomimetic amines.

The following compounds are of particular interest in that they havebeen shown to be eitective in causing in animals a selective block ofthe peripheral sympathetic (adrenergic) nervous system Without affectingthe peripheral parasympathetic nervous system and without causingganglion block:

Others of the compounds defined above also modify the actions ofthesympathomimetic amines. Examples of such compounds which exert ahypotensive effect are quaternary ammonium salts of:

2 2-dimethyl-1 :2 3 24-tetrahydroisoquinoline, for example the iodide;and

3,175,945 Patented Mar. 30, 1965 Z-methyl-Z-n-propyl-l :2 3 :4tetrahydroisoquinoline, for

example the iodide.

Other examples of such compounds may exert a mildly hypertensive effect.

The pharmacologicallyactive quaternary ammonium salts of1:2z324-tetrahydroisoquinoline as defined above may be provided as apharmaceutical or veterinary composition in a suitable form for dosage,which composit1on contains essentially at least one pharmacologicallyactive salt and which also comprises a pharmaceutical carrier base whichmay be a liquid, semi-solid or solid. Thus for example, the compositionmay be in a form suitable for parenteral administration which may besterile solutions, suspensions in water or other liquids,

with or Without the addition of soluble or insoluble diluents and/ orsolid or liquid excipients.

In clinical practice the compounds of the present invention willnormally be administered orally and in consequence, the preferredformulations are of the kind which are most suitable for oral ingestion.

Preparations for oral administration can be liquids or solids or anycombination of these forms such as solutions, suspensions, emulsions,elixirs, syrups, powders or tablets.

Pharmaceutical preparations for administration of the active therapeuticagents in unit dose form can take the form of compressed powders or of apowder enclosed in a suitable capsule of absorbable material such asgelatin. These compressed powders or tablets can take the form of theactive material admixed with suitable excipients and/ or diluents suchas starch, lactose, stear-ic acid, magnesium stearate, dextrin or thelike.

The pharmacologically active salt may be presented in the form of aresinate to give a relatively slow and even release of the drug whenacted upon by the normal contents of the gastro-intestinal tract, asdescribed in for example United Kingdom patent specifications No. 857,-193 and 857,194.

According to another'aspect of the invention, there is provided a methodof preparing the quaternary ammonium salts having the formula definedabove, which method comprises heating a N-substituted-1:22324-tetrathydroisoquinoline having the formula:

N-Rt NRg Ol i Q Q wherein R and R have the meanings defined above, withan allrylating agent of the formula R X or R X respectively, preferablyin the presence of an appropriate organic solvent, such as for exampleacetone or methyl ethyl ketone. The product either separates and can befiltered off, or is precipitated for example by the addition of ether.

The N-allyl-l 2:3 :4-tetrahydroisoquinoline starting material may beprepared from 1:2:3:4-tetrahydroisoquinoline by reaction with an allylhalide in the presence of a base, such as for example potassiumcarbonate, either alone or in a suitable solvent, such as for exampleacetone. The tertiary amine product is often contaminated with theunsubstituted tetrahydroisoquinoline and in this case may be separatedeither by fractional distillation or by the Hinsberg technique. Thetertiary amine starting material prepared in this manner may then bequaternized in the above described manner.

'The N-propargyl-l:213:4-tetrahydroisoquinoline starting material, whichis a new compound, may itself be prepared from 1:2:3:4-tetrahydroisoquinoline by reaction with 2:3-dibromoprop-l-ene,followed by dehydrohalogenation with a suitable base of theN-(Z-bromoprop-Z- ene)-1:2:3:4-tetrahydroisoquinoline so formed. Theresulting tertiary base may then be quaternized in the manner alreadydescribed.

Example 1 Example 2 A mixture of 2-methyl-l:2z3:4-tetrahydroisoquinoline(25 g.) ethyl-p-toluenesulphonate (37.2 g.) and methyl ethyl ketone (75ml.) was heated on a steam bath for 2 /z hours. On prolonged standing atroom temperature the solution deposited crystals. These were filteredoff, washed with methyl ethyl ketone, to give 2-ethyl-2-methyl- 1 :2 3i4-tetrahydroisoquinolinium p-toluene sulphonate, M.P. 102-106 C..Analysis.C, 65.67%; H, 7.26%; N, 4.10%. C1gH1gN.C7H7SO requires C, H,7.25%; N, 4.03

Example 3 Allyl bromide (12.1 g.) was added slowly to a solution of2-methy1-1:2:3:4-tetrahydroisoquinoline (14.7 g.) in methyl ethyl ketone(50 ml.) and the mixture heated on a steam bath for 1 hour. The syrupwhich separated was crystallized by trituration and was recrystallizedfrom isopropanol-ether to give'2-ally1-2-methyl-1:22324-tetrahydroisoquinolinium bromide M.P. l58-l60C. Analysis.- C, 58.4%; H, 6.79%; N, 5.26%; Br, 29.72%. C H NBr requiresC, 58.22%; H, 6.76%; N, 5.22%; Br, 29.80%.

Example 4 Propargyl bromide (11.9 g.) was slowly added to a solution ofZ-methyl 1:2: 3 :4 tetrahydroisoquinoliue (14.7 g.) in methyl ethylketone (100 ml.). A syrup settled out immediately and crystallized oncooling. The resulting product was filtered off and recrystallized fromethanol to give 2-methy1-2-propargyl-122:324-tetrahydroisoquinoliniumbromide, M.P. 195197 C. Analysis.- C, 58.82% H, 6.18%; N, 5.58%. C H NBrrequires C, 58.65%; H, 6.06%; N, 5.26%.

Example 5 Ethyl iodide (8 g.) was slowly added to a solution of2-ethy1-1:2:3:4 tetrahydroisoquinoline (8 g.) in methyl ethyl ketone (40ml.) and the mixture heated on a steam bath for 1 hour. The crystallineproduct was filtered off and recrystallized from isopropanol to give2:2-diethy1- 1:2:3:4-tetrahydroisoquinolinium iodide, M.P. 158-160 C.Analysis.C, 49.28%; H, 6.41%; N, 4.05%. C H NI requires C, 49.21%; H,6.35%; N, 4.42%

. Example 6 A mixture of 2ethyl-l:2;3.:4-tetrahydroisoquinoline (10.g.), n-propyliodide (11 g.) and methyl etheyl ketone (40 ml.) was heatedon a steam bath for 3 hours, cooled and ether added. The precipitatedsyrup crystallized on triturating with ether. Recrystallization fromisopropanol- 41 gave 2-ethyl-2-n-propyl-l:2:3:4:tetrahydroisoquinolinium iodide, M.P. 108-1l1 C. Analysis.C, 50.83%; H,6.63%; N, 4.45%; l, 37.87%. C I-1 511 requires C, 50.76%; H, 6.695%; N,4.23%; I, 38.31%.

Example 7 Allyl bromide (8 g.) was added slowly to a solution of2-ethyl-1:2:3:4-tetrahydroisoquinoline (10 g.) in methyl ethyl ketone(40 ml.) and the mixture heated on the steam bath for 1 hour. The syrupwhich separated was crystallized by trituration with ether.Recrystallization from ethanol-ether gave2allyl-2-ethyl-1:2:3:4-tetrahydroisoquinolinium bromide, M.P. 100 C.

Example 8 Allyl bromide (36.6 g.) was added slowly to 1:2:3:4-tetrahydroisoquinoline (39.9 g.) with cooling. Potassium carbonate (41.4g.) was then added and the mixture heated on a steam bath for 4 hours.Water ml.) was added to the cooled mixture followed by 10 N sodiumhydroxide (20 ml.). The oil which separated was isolated by etherextraction. The oil distilled at 114-l22 C/l2 mm., and from theinfra-red spectra thereof was shown to be a mixture of2-allyl-1:21324-tetrahydroisoquinoline and 1:223:4-tetrahydroisoquinoline. The oil was submitted to a Hinsbergseparation using sodium hydroxide and benzene sulphonyl chloride. The2-allyl-1:2:3:.4- tetrahydroisoquinoline did not form a benzenesulphonaniide and remained soluble in dilute hydrochloric acid.Basification of the acidic solution with 10 N sodium hydroxide liberatedthe 2-allyl-l:2z3z4-tetrahydroisoquinoline which distilled at 118122 C./12 mm.

Allyl bromide (8 g.) was slowly added to a solution in methyl ethylketone (40 ml.) of 2-allyl-lz2z3z4-tetrahydroisoquinoline (9 g.)prepared in the above manner, and the resulting mixture was heated on asteam bath for 2 hours. The precipitated syrup slowly crystallized ontrituration with ether. Recrystallization from isopropanol ether gave 2:2-diallyl-1 :2: 3 :4tetrahy-droisoquinolinium bromide, M.P. 1l5-1l8 C.Analysis.-C, 60.77%; H, 6.69%; N, 4.59%; Br, 27.7%. C H NBr requires C,61.24%; H, 6.85%; N, 4.76%; Br, 27.16%.

Example 9 A mixture of 2-ethyl-122:3:4-tetrahydroisoquinoline (10 g.),ethylene bromohydrin (10 g.) and methyl ethyl ketone (40 ml.) was heatedon a steam bath for 3 hours, cooled, and ether added. The resultingprecipitated syrup crystallized on trituration with ether.Recrystallization from ethanol-ether gave2-ethyl-2-(2'-hydroxyethyl)-l:2:

Y 3 :4-tetrahydroisoquinolinum bromide, M.P. 65-70 C.

Example 10 l22:3:4-tetrahydroisoquinoline (26.5 g.) was added slowlywhilst cooling to 80% formic acid (13 g.). 38% formalin solution (20 g.)was then run in and the resulting mixture was heated on a steam bath.When the evolution of CO had almost ceased, 3 mls. formic acid and 3mls. formalin were added and heating was continued for a further 2hours.

The mixture was then cooled and water (50 mls.) was added, Whereafter,the solution was rendered strongly basic by the addition of KOHsolution. The oil which separated was extracted with ether three timesand the combined ether extracts were washed twice with water, dried anddistilled. The N-methylated compound distilling at 108l12 C./ 16 mm. wascollected in a yield 0 17.0 g.

Ethyl iodide (10 mls.) was added to a solution in acetone (40 mls.) of2-methy1-1:2:3 :S-tetrahydroisoquinoline prepared as described above andthe resulting mixture was then heated on a steam bath until reaction Wascomplete. Ether was then added to the mixture and the solid which thenformed was collected in a yield of 17.0 g., M.P. 139- 142 C.

Recrystallization from alcohol-ether with charcoaling gave 2methyl-Z-ethyl-l:2z3:4-tetrahydroisoquinolinum iodide, MP. 140-14l C.Analysis.C, 47 9%; H, 6.0%; N, 4.7%. C N NI requires C, 47.5%; H, 6.0%;N, 4.6%.

Example 1] Methyl iodide g.) was added slowly to a solution of2-methyl-1:2:3 :4-tetrahydroisoquinoline (14.7 g.) in methyl ethylketone (50 ml. and the mixture heated .on a steam bath for l-hour. Thecrystalline product which formed was filtered off and recrystallizedfrom ethanol to give 2:2- dimethyl-1:2:3:4-tetrahydroisoquinoliniumiodide (15.0 g.) having M.P. 194196 C.

By way of further exemplification, other compounds which have been madein accordance with the invention include:

Example 12 2:3-dibromoprop-1-ene (30 g.) was slowly aded to an ice coldsolution of 1:2:3:4-tetrahydroisoquinoline (39.9 g.) in ether (160 ml.)and the mixture allowed to stand overnight at room temperature. Thecrystals of 122:3:4- tetrahydroisoquinoline hydrobromide were filteredoff and the ethereal solution distilled. N-(2-bromoprop-2-ene)-1:223:4-tetrahydrisoquinoline was collected at 96-l00 C./0.15 mm.

N- 2-bromoprop-2-ene) -1 22:3 z4-tetrahydroisoquinoline (31.8 g.) wasslowly added (over hour) to a solution of potassium hydroxide (14 g.) inethylene glycol (100 ml.), the temperature of the well agitated mixturebeing kept at 130140 C. The solution was allowed to cool to roomtemperature and then it was poured into water (300 ml.). The basic oilwas separated by ether extracderivatives may be used in preparingthepharmaceutical compositions instead of the 2-ethyl 2-methyl-paratoluenesulphonate derivative providing that they are within the definition ofthe general Formula I and that the compounds and compositions containingthem modify the. action of sympathomimetic amines.

We claim:

1. ,A- method of selectivelyblocking the peripheral sympathetic nervoussystem of animals without affecting the peripheral parasympatheticnervoussystem, which comprises administering to the animal a nontoxicsalt selected from the group consisting of salts with a nontoxic anionof Z-methyl-Z-ethyl-l :2: 3 :4-tetrahydroisoquinoline; 2methyl-2-allyl-122z3 :4-tetrahydroisoquinoline; 2,2,-diethyl 122:3:4-tetrahydroisoquinoline and 2-ethyl-2-(2- hydroxyethyl) -1 2: 3:4-tetrahydroisoquinoline.

2. A method of selectively blocking the peripheral sympathetic nervoussystem of animalsv without affecting the peripheral parasympatheticnervous system, which tion, the ether solution being dried and distilledto give N-propargyl-1:2:3:4-tetrahydroisoquinoline, B.P. 132-8 C./15 mm.Treatment of the base with ether and ethereal hydrogen chloride gaveN-propargyl-1:2:3:4-tetrahydroisoquinoline hydrochloride, M.P. 199 C.after recrystallization from ethanol. The propargyl tertiary base andits acid addition salts are new compounds and may, if desired, beincorporated into pharmaceutical preparations for administrationpurposes, just as described for the quaternary compounds.

To convert the tertiary base into a quaternary compound in accordancewith the invention, methyl bromide (4.75 g.) was slowly added to an icecold solution of N propargyl-1z2t3:4-tetrahydroisoquinoline (8.55 g.) inmethyl ethyl ketone ml.). A syrup separated out which slowlycrystallized. This was filtered 01f and recrystallized from ethanol togive 2-methyl-2-propargyl-1: 2:3:4-tetrahydroisoquinolinium bromide,M.P. 195-7 C.

Example 13 Tablets were prepared by granulating and compressing thefollowing ingredients in accordance with known pharmaceuticaltechniques. Each table contained:

2 ethyl 2-methy1-1:2:3:4rtetrahydroisoquinolinium para-toluenesulphonate 200 Calcium phosphate n 280 Lactose 200 Ethyl cellulose 9Maize starch (dried) 21 Magnesium stearate 10 Other 2 2-disubstituted-12: 3 4-tetrahydroisoquinoline comprises administering to the animal asalt with a nontoxic anion ofZ-methyl-Z-ethyl-lz2z3z4-tetrahydroisoquinoline.

3. A method of selectively blocking the peripheral sympathetic nervoussystem of animals without affecting the peripheral parasympatheticnervous system, which comprises administering to the animal a salt witha nontoxic anion of 2-methyl-2-allyl-1:2,3,4-tetrahydroisoquinoline.

4. A method of selectively blocking the peripheral sympathetic nervoussystem of animals without affecting the peripheral parasympatheticnervous system, which comprises administering :to the animal a salt witha nontoxic anion of 2-2-diethyl-1 2:3 :4-tetrahydroisoquinoline.

5. A method of selectively blocking the peripheral sympathetic nervoussystem of animals without affecting the peripheral parasympatheticnervous system, which comprises administering to the animal a salt witha nontoxic anion of 2-ethyl-2- (Z'hydroxyethyl -1. z 2 z 3:4-tetrahydroisoquinoline.

6. The method of reducing the blood pressure of animals without causingganglion block which comprises administering to the animal a nontoxicsalt selected from the group consisting of salts with a nontoxic anionof 2-methyl-2-ethyl-1 2: 3 :4-tetrahydroisoquinoline; 2-methyl 2 allyl112:3 :4 tetrahydroisoquinoline; 2 2 diethyl-l :2: 3:4-tetrahydroisoquinoline; and 2-ethyl-2-(2- hydroxyethyl) -1 2 34-tetrahydroisoquinoline.

7. The method of reducing the blood pressure of animals without causingganglion block which comprises administering to the animal a salt with anontoxic anion of 2-methyl-2-ethyl-1 :2: 3 :4-tetrahydroisoquinoline.

8. The method of reducing the blood pressure of animals without causingganglion block which comprises administering to the animal a salt with anontoxic anion of 2-methyl-2-allyl-l :2: 3 :4-tetrahydroisoquinoline.

9. The method of reducing the blood pressure of animals without causingganglion block which comprises administering to the animal a salt with anontoxic anion of 2-2-diethyl-1 :2: 3 4-tetrahydroisoquinoline.

10. The method of reducing the blood pressure of animals without causingganglion block which comprises administering to the animal a salt with anontoxic anion of 2 ethyl 2-(2' hydroxyethyl) 1:2: 3:4tetrahydroisoquinoline.

11. A composition useful for the treatment of hypertension in animals,consisting essentially of a nontoxic salt selected from the groupconsisting of salts with a nontoxic anion of2-methyl-2-ethyl-l:2z3z4-tetrahydroisoquinoline; 2 methyl 2 allyl1222324 tetrahydroisoquinoline; 2-2-diethyl-1 :2: 3:4-tetrahydroisoquinoline; and 2 ethyl 2 (2' hydroxyethyl) 122:3 :4tetrahydroisoquinoline; and a therapeutically acceptable carrier.

12. A composition useful for the treatment of hypertension in animals,consisting essentially of a salt with a nontoxic anion of2-methyl-2-ethyl-1z2z3z4-tetrahydroisoquinoline; and a therapeuticallyacceptable carrier.

145A composition useful for the treatment of hypertension in animals,consisting essentially of a salt With a nontoxic anion of2-2-diethyl-1:2:3:4-tetrahydroisoquinoline; and a therapeuticallyacceptable carrier.

15. A composition useful for the treatment of hypertension in animals,consisting essentially of a salt with a nontoxic anion of2-ethy1-2-(2-hydroxyethyl)-122:3:4- tetrahydroisoquinoline; and atherapeutically acceptable carrier.

References Cited in the file of this patent UNITED STATES PATENTS DeBenneville Sept. 27, 1955 2,957,872 Huebner Oct. 25, 1960 FOREIGNPATENTS Great Britain Jan. 16, 1952 OTHER REFERENCES p Robinson: J.Organic Chem., vol. 16, pp. 1911-1919 (1951).

Hjort et at: J. Pharmacol, vol. 76, p. 71 (1942).

Torossionz Comptes Rendus, pp. 1313-14 (1952), vol. 235.

Skita: Chemische Berichte, vol. '57,- pp. 1977-1982 (1924 p ChemicalAbstracts, vol. 54, entry 21150a, 1960 (citing Awe et. al., Chem. Ber.,vol. 90, pages 1997-2003 (1957).

Websters New International Dictionary of the English Language, SecondEdition, published'by G. andC. Merriam Co., Springfield, Mass, 1939.

11. A COMPOSITION USEFUL FOR THE TREATMENT OF HYPERTENSION IN ANIMALS,CONSISTING ESSENTIALLY OF A NONTOXIC SALT SELECTED FROM THE GROUPCONSISTING OF SALTS WITH A NONTOXIC ANION OF2-METHYL-2-ETHYL-1-1:2:3;4-TETRAHYDROISOQUINOLINE; 2 - METHYL - 2 -ALLYL - 1:2:34 - TETRAHYDROISOQUINOLINE;2-2-DIETHYL-1:2:3:4-TETRAHYDROISOQUINOLINE; AND 2 - ETHYL - 2 - (2''-HYDROXYETHYL) - 1:2:3:4 - TETRAHYDROISOQUINOINE; AND A THERAPEUTICALLYACCEPTABLE CARRIER.